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Research Articles

Trastuzumab causes antibody-dependent cellular cytotoxicity–mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance

Departments of ¹ Biophysics and Cell Biology, ² Dermatology, ³ Medical Chemistry, ⁴ Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary; and ⁵ Institute of Medical Technology, University and University Hospital of Tampere, Tampere, Finland

Requests for reprints: János Szöllösi, Medical and Health Science Center, Department of Biophysics and Cell Biology, University of Debrecen, 1 Egyetem sqr., Debrecen 4010, Hungary. Phone: 36-52412623; Fax: 36-52532201. E-mail: szollo{at}dote.hu

Abstract

Trastuzumab is a recombinant antibody drug that is widely used for the treatment of breast cancer. Despite encouraging clinical results, some cancers are primarily resistant to trastuzumab, and a majority of those initially responding become resistant during prolonged treatment. The mechanisms of trastuzumab resistance have not been fully understood. We examined the role of antibody-dependent cellular cytotoxicity (ADCC) using JIMT-1 cells that are ErbB2 positive but intrinsically resistant to trastuzumab in vitro. Unexpectedly, in experiments mimicking adjuvant therapy of submacroscopic disease in vivo (JIMT-1 cells inoculated s.c. in severe combined immunodeficiency mice), trastuzumab was able to inhibit the outgrowth of macroscopically detectable xenograft tumors for up to 5–7 weeks. The effect is likely to be mediated via ADCC because trastuzumab-F(ab')₂ was ineffective in this model. Moreover, in vitro ADCC reaction of human leukocytes was equally strong against breast cancer cells intrinsically sensitive (SKBR-3) or resistant (JIMT-1) to trastuzumab or even against a subline of JIMT-1 that was established from xenograft tumors growing despite trastuzumab treatment. These results suggest that ADCC may be the predominant mechanism of trastuzumab action on submacroscopic tumor spread. Thus, measuring the ADCC activity of patient's leukocytes against the tumor cells may be a relevant predictor of clinical trastuzumab responsiveness in vivo. [Mol Cancer Ther 2007;6(7):2065–72]

Grant support: Hungarian Academy of Sciences grants OTKA T043061 and F049025, European Commission grants LSHB-CT-2004-503467 and LSHC-CT-2005-018914, Finnish Cancer Foundation, Sigrid Juselius Foundation, and Tampere University Hospital Research Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M. Barok and J. Isola contributed equally to the work.

Received 12/11/06; revised 4/10/07; accepted 5/25/07.